Over 1.6 million new cancer diagnoses and about 580,000 deaths from cancer are expected to occur in the United States in 2012. Cancer is currently the second most common cause of death in the US, trailing behind the leading cause, heart disease. Although various new cancer treatments have been developed over the past decade, the five-year relative survival rate for all cancers diagnosed between 1999 and 2006 is 68%, with estimated deaths of 28% and 26% for lung cancer in males and females, respectively, 15% for breast cancer in females, and 11% for prostate cancer. Such statistics reflect a critical need for further advances in available treatments.
Personalized medicine has revolutionized the trial and error process of current medical treatment and improved patient response rates by utilizing biomarker profiles to more effectively predict a patient's response to a drug and to reduce the time spent in ineffective treatment that permits disease to advance. At least in certain cases such an approach has allowed for a more targeted and thus more effective treatment, highlighting the potential benefit of use of biomarkers in customizing patient treatment regimens to increase therapy success rates.
For example, at the 47th Annual Meeting of the American Society of Clinical Oncology (June, 2011), Tsimberidou et at from the MD Anderson Cancer Center presented a study describing the success of treatment regimens targeting PIK3CA, mTOR, BRAF, MEK, multikinases, KIT or EGFR in 175 patients with one genetic aberration. This study showed that the response rate was 27% with matched targeted therapy versus 5% observed for patients treated with non-matched therapy. Other markers with at least some success for improvement in treatment outcome for use in personalized medicine were described by Duffy and Crown (Clinical Chemistry, 2008, 54(11):1770-1779). This and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Faulty chromosomal segregation and uncontrolled mitotic proliferation are hallmarks of neoplastic disease. However, despite the availability of an increasing number of cancer markers, there remains a lack for markers indicative of susceptibility to drugs that target spindle and kinetochore regulation or mitotic checkpoint control. Hec1, for example, is a critical component in spindle checkpoint signaling that is highly expressed in cancer and helps assure correct segregation of chromosomes during cell division. Several potentially powerful Hec1 inhibitors have recently been reported (see e.g., WO 2011/115998 to Lau and Huang; Qiu et at in J. Med. Chem., 2009, 52(6):1757-1767; Wu et at in Cancer Res., 2008 Oct. 15, 68(20):8393-9). While at least some of the compounds have shown promising results, there is, however, no guidance as to any biomarkers that would be indicative of increased treatment success with such compounds.
Thus, there is still a need for biomarkers for cancers responsive to modulators of Hec1 activity.